Displacement of insulin-like growth factors from their binding proteins as a potential treatment for stroke.
Insulin-like growth factors I and II (IGF-I and IGF-II) play an important role in normal growth and brain development and protect brain cells from several forms of injury. The effects of IGFs are mediated by type-I and type-II receptors and modulated by potentially six specific binding proteins that form high-affinity complexes with IGFs in blood and cerebrospinal fluid (CSF) and under most circumstances inactivate them. Because brain injury is commonly associated with increases in IGFs and their associated binding proteins, we hypothesized that displacement of this large "pool" of endogenous IGF from the binding proteins would elevate "free" IGF levels to elicit neuroprotective effects comparable to those produced by administration of exogenous IGF. A human IGF-I analog [(Leu24, 59, 60, Ala31)hIGF-I] with high affinity to IGF-binding proteins (Ki = 0.3-3.9 nM) and no biological activity at the IGF receptors (Ki = >10,000 nM) increased the levels of "free, bioavailable" IGF-I in the CSF. Intracerebroventricular administration of this analog up to 1h after an ischemic insult to the rat brain had a potent neuroprotective action comparable to IGF-I. This novel strategy for increasing "free" IGF levels in the brain may be useful for the treatment of stroke and other neurodegenerative diseases.
Loddick
S A
SA
Neurocrine Biosciences, Inc., San Diego, CA 92121, USA.
Liu
X J
XJ
Lu
Z X
ZX
Liu
C
C
Behan
D P
DP
Chalmers
D C
DC
Foster
A C
AC
Vale
W W
WW
Ling
N
N
De Souza
E B
EB
D000818:Animals; D001667:Binding, Competitive; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000378:metabolism*; D008024:Ligands; D008297:Male; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley
D018969:Insulin-Like Growth Factor Binding Proteins; D008024:Ligands; D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I